CA2049176A1 - 6-substituted-hexahydrobenz [cd] indoles - Google Patents

Abstract

Abstract The present invention provides 4-amino-6-substituted-hexahydrobenz[cd]indoles which are useful in treating disease states which can be benefited by an alteration of 5-HT1A receptors.

Description

TIT~

6-SUBSTITUTED-HEXAHYDROBENZ~CD]INDOLES

Field of the_Invention This invention relates to the fields of synthetic organic chemistry and pharmaceutical chemistry and involves hexahydrobenz[cd]indoles which are useful in treating conditions requiring regulation L0 of the serotonin function in the body.

BackgrQ~nd of th~ Inv~.ntion Over the last several years it has become apparent that the neurotransmitter serotonin (5-hydroxytryptamine -- 5-HT) is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermoregulation, sleep, sexual behavior, anxiety, depression, blood pressure lowering and hallucinogenic behavior [Glennon, R. A., .~. Med~ ~h~m~, lQ, 1 (1987)].
It has been recognized that there are multiple types of 5-HT receptors. These receptors have been classified as 5-HT1, 5-HT2, and 5-HT3 receptors, with the former being further divided into the sub-classes 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D. The :: .

~-8265A 2 ~0~9~7~

binding affinity of a compound for one or more 5-HT
receptors can provide a desirable physiological effect or minimize an undesirahle effect. Therefore it is desirable to provide compounds which can bind to 5-HT
receptors to act as serotonin agonists or antagonists.
Flaugh in U.S. Patent No. 4,576,959 (issued 1986) disclosed a family of 6-substituted-4-dialkylamino-l,3,~,5-tetrahydrobenz[cd]indoles which are described as central serotonin agonists. Leander in U.S. Patent 4,745,126 (1988) disclosed a method for treating anxiety in humans employing a 4-substituted-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide derivative.
Certain indolines have been reported, as in U.S. Patent No. ~,110,339 of Bach e~ al. (197~), Flaugh et al., J. Med. Che~.. ~1, pp 1746-1753 (1988), Flaugh in U.S. Patent No. 4,576,959 and ~uropean Patent Ap-plication 153083 (published 1985). These were used as intermediates in the preparation of the corresponding indoles.
It has now been found that certain 6-sub-stituted- and particularly 6-acyl-substituted-4-amino-hexahydrobenz[cd]indoles (indolines) particularly certain stereoisomers of such indolines are useful in treating conditions requiring modification of serotonin function in the body.

Summarv of the I~vention This invention relates to a compound of the Formula I

' ,: :, `

~', 7~
~N p~1 R2 F~3N~
~1 I
wherein:
R1 is hydrogen, C1-C~ alkyl, C3-C4 alkenyl, cyclopropylmethyl, phenyl-s~stituted C1-C4 alkyl, - CoR4 r - ( CH2) nS(Cl-C4 alkyl), or -(CH2) nCoNR5R6;
R2 is hydrogen, C1-C4 al]cyl, C3-C4 alkenyl, or cyclopropylmethyl;
R3 iS hydrogen, Cl-C4 alkyl or an amino-blocking group;
n is 1-4;
R4 is hydrogen, C1-C4 alkyl, Cl C4 haloalkyl, C1-C4 alkoxy or phenyl;
R5 and R6 are independently hydrogen, a C1-C4 alkyl, or a C~-C8 cycloalkyl;
R7 iS Cl-C8 alkyl, substituted C1-C8 alkyl, aryl, substituted aryl, aryl (Cl-C4 alkyl), substituted aryl (Cl-C4 alkyl), C3-C7 cycloalkyl-substituted methyl, or C3-C7 cycloalkyl with the proviso that when A is C-C then R7 is Cl-C7 alkyl, substituted Cl-C7 alkyl, aryl, aryl (Cl-C3 alkyl), substituted aryl, substituted aryl (Cl-C3 alkyl), or C3-C7 cycloalkyl;
A is C=O, CHOH or C-C; and pharmaceutically acceptable salts thereof.
In a further embodiment, the instant invention comprises a compound of Formula I wherein (a) R1, and ~2 are independently ~ydrogen or a Cl-C4 alkyl;
(b) R3 is hydrogen;
(C) R7 iS Cl-C8 alkyl, substituted C1-C~ alkyl, phenyl, phenyl (C1- C4 alkyl);
(d) n is 2-4; and .

X-8265A 4 20~17~

(e) A is C=O; and pharmaceutically acceptable salts thereof.
The invention also provides a pharmaceutical formulation comprising a compound of Formula I and a pharmaceutically acceptable excipient therefor.
A further embodiment of the invention is a method for effecting a biological response at a 5-HT
receptor by adminlstering an effective amount of a compound of Formula I. Further embodiments involve the treatment of disease states with re~uire regulation of serotonin function in the body.

Detailed Descriptio~ of tk~ In~en~iQn As used herein, the term "alkyl" represents a straight or branched alkyl chain having the indicated number of carbon atoms. For example, "Cl-C~ alkylll groups are methyl, ethyl, n-ProPyl, isopropyl, ~-butyl, sec.-butyl, isobutyl and ~gr~-butyl. "Cl-C8 alkylll -groups include those listed for Cl-C4 alkyl as well as ~-pentyl, 2-methylbutyl, 3-methylbutyl, g-hexyl, 4-methylpentyl, ~-heptyl, 3-ethylpentyl, 2 methylhexyl, 2,3-dimethylpentyl, ~-octyl, 3-propylpentyl, 6-methyl-heptyl, and the like.
The term " C3 - c4 alkenyl" refers to olefinically unsaturated alkyl groups such as -CH2CH=CH2 -CH(CH3)CH=CH2, -CH2CH2CH=CH2 and the like.
The term ~aryl~ means an aromatic carbocyclic structure ha~ing one or two rings with a total of six to ten carbon atoms in the rings. Examples of such ring structures are phenyl, naphthyl, indan~l, and the like.
The term l'cycloalkyl" means an aliphatic carbocyclic structure ha~ing the indicated number of carbon atoms in the ring. For example, the term " C3 - C7 cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term "aryl (C1 C4 alkyl)" means an , ~ , ~ ;, ~9~7~

aromatic carbocyclic structure joined to a Cl-C4 alkyl group. Examples of such groups are benzyl, phenylethyl, a-methylbenzyl, 3-phenylpropyl, a-naphthylmethyl, ~-naphthylmethyl, 4-phenylbutyl, and the like. Similarly the term ~aryl (C1-C3 alkyl)"
means an aromatic carbocyclic st m cture joined to a C
-C3 alkyl.
The C1-C8 alkyl, the aryl, the aryl (C1-C4 alkyl) , and aryl (C1-C3 alkyl) groups can be substituted by one or two moieties. Typical aryl and/or alkyl substituents are C1-C3 alkoxy, halo, hydroxy, C1-C3 thioalkyl, and the like. Moreover, the aryl, aryl (C1-C4 alkyl) and aryl (C1-C3 alkyl) groups can also be substituted by a Cl-C3 alkyl or a trifluoromethyl group.
In the foregoing, the term "C1-C3 alkyl"
means any of methyl, ethyl, ~-propyl, and isopropyl;
the term "CL-C3 alkoxy" means any of methoxy, ethoxy, n-propoxy, and isopropoxy; the term ~halo" means any oE
fluoro, chloro, bromo, and iodo; and the term "C1-C3 thioalkyl~ means any of methylthio, ethylthio, n-propylthio, and isopropylthio.
Examples of substituted Cl-C8 alkyl are methoxymethyl, trifluoromethyl, 6-chlorohexyl, 2-bromopropyl, 2-ethoxy-4-iodobutyl, 3-hydroxypentyl, methylthiomethyl, and the like.
Examples of substituted aryl are ~-bromo-phenyl, ~-iodophenyl, ~-tolyl, n-hYdroxYphenYl, ~-(4-hydroxy)naphthyl, ~-(methylthio)phenyl, m- trifluoro-methylphenyl, 2-chloro-4-methoxyphenyl, a-(5-chloro)-naphthyl, and the like.
Examples of the substituted aryl (Cl-C4 alkyl) are ~-chlorobenzyl, Q-methoxybenzyl, m-(methylthio)-a-methyl-benzyl/ 3-(4l-trifluoromethylphenyl)-propyl, o-iodobenzyl, ~-met~ylbenzyl, and the like.
The term "amino-blocking group" is used as it is fre~uently used in synthetic organic chemistry, to refer to a group which will prevent an amino group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed from the amine when it is desired to do so.
Such groups are discussed by T. W. Greene in chapter 7 of Pro~ective Groups in Orqanic Synthesi~, John Wiley and Sons, New York, 1981, and by ~. W. Barton in chapter 2 of PrQtective Grou~s in Orgam ç Chemistry. J.
F. W. McOmie, ed., Plenum Press, New York, 1973, which are incorporated herein by reference in their entirety.
Examples of such groups include those of the formula -COOR where R includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, l-methyl-l-phenylethyl, isobutyl, ~-butyl, ~-amyl, vinyl, allyl, phenyl, benzyl, ~-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl, benzyl and substi~uted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenyl-methyl trityl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and p-methoxybenzoyl; and other groups such as methanesulfonyl, ~-toluenesulfonyl, ~-bromobenzenesul~onyl, ~-nitrophenylethyl, and p-toluenesulfonylaminocarbonyl. Preferred amino-blocking groups are benzyl (-CH2C6H~), trityl, acyl [C(O)R] or SiR3 where R is Cl-C4 alkyl, halomethyl, 2-halo-substituted alkoxy, or phenyl.
The compounds of the instant in~ention have at least 2 chiral centers and therefore at least four stereoisomers can exist for each. Chiral centers exist at position 2a and 4 as in Formula I. If a substituent group contains a chiral cen~er, then additional stereo-isomers can of course exist. Racemic mixtures as well as the substantially pure stereoisomers of Formula I
are contemplated as within the scope of the present invention. The term ~substantially pure" refers to at least about 90 mole percent, more preferably at leas~
about 95 mole percent, most preferably at least about 98 mole percent of the desired stereoisomer being present compard to the other stereoisomers present.
Particularly preferred stereoisomers of Formula I are those in which the configuration of the chiral center at position 2a is S and at position 4 is R, i.e., 2aS, 4R.
The terms "~" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of chiral center. The term ~'R" refers to "rightl~ and refers that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" or l'left'l refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (heaviest isotope first). A partial list of priorities and a discussion of stereo chemistry is contained in the book: The Vocabulary Qf Qrganic Chemi~trv Orchin, et al. John Wiley and Sons Inc., publishers, page 126, w~lich is incorporated herein by reference.
While all of the compounds of the in~ention are useful for the purposes taught herein, certain of the present compounds are preferred for such uses.
Preferably R1 and R2 are both C1-C~ alkyl, and especially ~-propyl. R3 is preferably hydro~en, R7 is preferably C1- C4 alkyl, substituted Cl- C4 alkyl, or C3 -C7 cycloalk~l. Although compounds in which A is CHOH
or CaC have activity, their primary utility is as intermediates in the preparation of compounds in which A is C=O. Other preferred aspects of the present - X-8265A 8 ~ 37~

invention are noted hereinafter.
As pointed out above, this invention includes the pharmaceutically-acceptable salts of the compounds of Formula I. Since the compounds of this invention are amines, they are basic in nature and accordingly react with any number of inorganic and organic acids to ~orm pharmaceutically acceptable salts such as hydro-chloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and others, as well as salts derived from non-toxic organic acids such as aliphatic mono and dicarboxylic acids, amino acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acid, aroma~ic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, capry-late, acrylate, formate, tartrate isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, hippurate, benzoate, chlorobenzoate, met~ylbenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, b-hydroxybutyrate, glycolate, malate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mesylate.
The following list illustrates representative compounds of the present invention:

4-(di-~-propylamino)-6-acetyl-1,2,2a,3,4,5-hexahydrobenz[cd~indole;
4-(di-n-propylamino)-6-(2,2-dimethylpropanoyl!-1,2,2a,3,4,5-hexahydrobenz[cd]indole;
4~(diethylamino)-6-propanoyl-1,2,2a,3,4,5-~ X-8265A 9 2~ 7~

hexahydrobenz[cd]indole;
4-(di-n-propylamino)-6-benzoyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole;
(2aS,4R)-4-(~-propylamino)-6-(2-methylpropanoyl)-1,2,2a,3,4,5-hQxahydrobenz[cd]indole;
~.-methyl-4-(di-~-propylamino)-6-benzoyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole;
l-methyl-4-(n-propylamino)-6-(3-methylbutanoyl)-1,2,2a,3,4,5-hexahydrobenz~cd]indole;
(2aS,4R)-4-(di-~-propylamino)-6-(2,2-dimethyl-propanoyl)-1,2,2a,3,4,5-hexahydrobenz[cd]indole;
(2aS,4R)-4-(di-n-propylamino)-6-benzoyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole; and 4-(N-~-propyl-N-cyclopropylmethyl)amino-6-propanoyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole;
(2aS,4S)-4-(di-n-propylamino)-6-acetyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole;
(2aS,4R)-4-(di-~-propylamino)-6-(2-phenylethanoyl)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; and Scheme 1 depicts a process for preparing compounds of the present in~ention wherein Rl, R2 and R7 are as defined abo~e and Z is an amino-blocking group as defined hereinabove.
According to one route of this pro~ess, a 4-amino-6-bromohexahydrobenz[cd]indole 1 is combined with an e~uimolar to slight excess amount of potassium hydride in diethyl ether. The reagents are generally combined at a cold tempera~ure, typically in the range of about -20C to about 10C, pre~erably at about 0C.
The resulting mixture is cooled to a temperature in the range of about -100C to about -60C, preferably at about -78C, and cornbined with a lithiatin~ reagent, preferably in at least a two molar excess amount.
Suitable lithiating reagents include ~-butyllithi~, the preferred t-butyllithium, and other similar organo-lithium compounds is preferred. The reaction is - X-8265A 10 ~7~ -preferably conducted at a temperature in the range of about -100C to about -20C~ more preferably at about -60~ to about -40C.
The 4-amino-6-lithiohexahydrobenz~cd]indole thus prepared is then contacted with an appropriate electrophile such as L-C(o)R7 wherein ~7 iS defined above and L is a good leaving group such as chlorine bromine, methoxy, phenoxy and the like. Typically, a solution of the compound ~ at a temperature in the range of about -100C to about -60C, preferably at about -80C, is added to a solution of this reagent in a mutual solvent. If an excess amount of the electrophile is employed in the reaction, the 1-amino group will also be acylated (ie Z is the acyl group R7C(o) in compound ~) and a subse~uent hydrolysis reaction is required to provide the free indoline, I.
A 1:1 ratio of electrophile to lithiated indoline (compound 2) can be used to minimize acylation of the l-nitrogen. The reaction is preferably conducted at a temperature in the range of about -40C to about 10C.
The desired compound iæ purified by quenching the reaction mixture with, for example, ice water when a 1:1 ratio is used. With a higher ratio in which significant l-acylation is obtained, the product is hydrolyzed using an acid such as sulfuric acid or a base such as sodium hydroxide. The mixture is then washed with a water-immiscible organic solvent. The organic phase is extracted with acid; the aqueous phases are combined and made basic; and the desired compound is extracted with a water immiscible organic solvent. The organic solvent is then concentrated, typically under vacuum, and the desire~ compound I is further purified, if necessary, by standard procedures.
In an alternative route, the l-nitrogen can be "blocked" or l'protectedll before initiating the metallation reaction. A blocking group (depicted as :
, ~

:

X-8265A 11 ~7~i "Z") such as SiR3, C(O)R, or CH2(C6H~) where R is C3-C4 alkyl or phenyl (C6H5) is preferably used to provide compound 1~ Compound la is then reacted with a lithiating agent as described above to provide compound ~a. Compound ~a can then be acylated by contacting with a suitable electrophile as described hereinabove.
The resultin~ compound 3a is then deprotected by hydrolysis when Z is SiR3. When Z is benzyl, compound ~ can be subjected to hydrogenolysis over a catalyst such as palladium to remove the benzyl group. The desired compound is isolated by standard conditions and purified by crystallization from common solvents or column chromatography over solid supports such as silica gel or alumina.
An alternative synthesis of the compounds I
is depicted in Scheme 2 and involves treatment of the 6-lithio derivatives 2 and ~a (depicted in Scheme 1) with an aldehyde~ R7CHo, to form an alcohol 4 or ~.
Oxidation of the alcohol can be accomplished with oxidants known to those skilled in the art for such purposes such as pyridinium chlorochromate, dimethyl-sulfoxide and oxalyl chloride, an aqueous solution of chromic acid and sulfuric acid, and the like. Depro-tection of the 1-amino group provides the free amine 2S compounds I.

- X-8265A 12 ~ 0~917~i ~cheme 1 Br Br ,NR1R2 ~ NR1R2 I!~J Protect~ I~J
HN~ 1 ,N~ ~
KH

¦ LiC4Hg 1 ~

~,NR1R2 ~NR1Rr 1 ~ 1 ~ :

R7~o ~7~
NR1R2 ~ NR1R2 ~t ~
-~N~ x ,N~

~;' ' -2~ L7~

Scheme 2 Li Li ~g~NR1R2 ~,NR1~2 KN ~ ZN ~

lR7CHo lR CHO

\/ R7\/oH
p~2 ~,N ~1 R2 'r _~Deprotect ~
HN I ~ ZN I ~a I [o]
[o]

R7~o R7~o NP~1R2 ~ R2 ~ Deprot~ct ~J
HN I ZN

The alcohol intermediates 4 and ~a can alter-natively be prepared as depicted in Scheme 3 by addition of an organometallic reagent (R7M) such as an alkyl lithi~m R7Li or a Grignard reagent R7MgX to aldehyde 5 and ~a, respectively.

, x-826sA 14 Z~4917~

S~heme 3 ~NRIR2 CHO N~ R2 ~ M 1R7-M

\~ R7~oH
~NRlR2 ,~ R1R2 ~lJ ~ ~U
T T
HN~ Deprotect l l Various routes can be used to prepare aldehydes 5 and ~a. The methods disclosed herein are not intended to be exhaustive and other procedures may be apparent to those skilled in the art. One route involves treating 6-lithioderivatives ~ and ~a with dimethylformamide followed by aqueous work up. Anoth~r method depicted in Scheme 4 involves the preparation of the 6-nitrile deriva~ive ~ followed by partial reduction and hydrolysis.

, ..

- . :

X-8265A 15 ~ 7 ~cheme 4 NR1~2 N~1R2 E~r~H cuc I N~H

B~ z 6 (~,N H2 Hl\l NRlR2 NR1~2 h H 3~1 H2SO4 )( h H
H~ -- -D H ~

E~z 7 H s The l-benzoyl-6-bromo-derivative 1 is con-tacted with a mixture of cuprous cyanide and cuprous iodide in dimethylformamide at about 140C. The re-sulting 6-nitrile ~ is llydrogenated over Pd/C in the presence of semicarbazide to provide the 6-semicarbazone, compound 7. This is hydro:lyzed using sulfuric acid to provide aldehyde ~.
In an alternative method of preparation, depicted in Scheme 5, the 6-nitrile derivative ~ is contacted with a reducing agent [H] such as diisobutyl-aluminum hydride. The resulting aldehyde ~ can be contacted with an organometallic reagent such as a Grignard reagent, R7MgBr, to provide alcohol ~a which is oxidized as described hereinabove to the l-blocked-6-acyl derivative ~.

: :
, . ; ~
:

~h~

C~NRlye ~NR1RZ

Z-N ~ Z-N ~

¦R7MgBr I 7 R MgBr R~NR~RZ R¢~NRlRZ

ZN ;~ ZN 4a Another method of preparation of compounds of Formula I involves the Friedel-Crafts acylation of the 6-~ indoline ~ as depicted in Scheme 6. The indoline 8, wherein R1~ R2 and Z are as defined hereinabove, is contacted with an acylating agent such - ,. . .
:

,. . : . ' ~:' ' X-8265A 17 ~9~7~

~çhçme 6 o N~1 R2 Lewis Acld /ydrolysis R7- ~/
~NRl R2 HN
aæ a carboxylic acid anhydride [(R7Co) 2~ or a carboxylic acid halide, particularly the acid chloride R7C(O)Cl, in the presence of a Lewis ACid. Preferred Lewis Acids include aluminum chloride, aluminum bromide, BF3, SnCl4, HF, TiCl~, and the like. The reaction is preferably conducted in a solvent commonly used for such acylation reactions, such as nitrobenzene, and the like. The reaction is normally conducted at a temperature in the range of 20C to reflux. Preferably the 1-amino group is protected with a blocking group depicted as Z in Scheme 6. A
preferred blocking group is the benzoyl group. The blocking group can be removed from compound ~a by hydrolysis, preferably using a base such as sodi~
hydroxide, to provide compound I.
Alternatively, certain com~ounds of Formula I
can be prepared using the 6-iodo derivative ~ as , X-826sA 18 depicted in Schemes 7 and 8 wherein R1, R2 and Z are as defined hereinabove. In Scheme 7 a method is shown in which a 6-alkyne derivative is prepared. This method provides 6-acyl compounds in which there is a methylene group adjacent to the carbonyl group. In this method the 1-amino group is protected with a group (represented by Z) such as a benzoyl group. This compound ~ is contacted with a palladium catalyst Pd(PPh3) 4 [where Ph is phenyl] and the tin alkyne compound R7a-C3C-Sn(CH3)3. R7a is a Cl-C7 alkyl, substituted Cl-C7 alkyl, aryl, aryl (Cl-C3 alkyl), substituted aryl, substituted aryl (C1-C3 alkyl), or C3-C7 cycloalkyl group. This reaction is normally conducted in a solvent such as toluene at an elevated temperature, eg. about 100C. Typically an excess of the tin alkyne is used along about 0.25 equivalents of the palladium compound based on compound ~. The 6-alkyne lQ is then contacted with HgS0~ in water or with a~ueous acid to provide the ketone 11. The 1-blocking group can be removed by hydrolysis with base as described above to provide compound I.

7~
x-826sA 19 Scheme 7 R7a P7-C-C-Sn(Ca3)3 ~ ,NR1RZ
;Z-N ~ Z-N L~

~120 HgSO4 R7a C~NRl R2 R7a-CH2 C~ NR~ RZ

HN I ~-N 11 In Scheme 8 a preparative method is depicted in which a vinyl ether is reacted with the 6-iodo derivative 9.
R1, R2 and Z are as defined hereinabove wi~h Z preferably a benzoyl group, except as provided below. This method provides a 6-tl-alkoxyalkenyl)derivative ~1 which can then be hydrolyzed and deprotected to provide the desired con~oound of Formula I. Alternatively, ~he derivative 81 can be deprotected, with for example butyl lithium, and then the vinyl group hydrolyzed. In this method the 1-amino group is protected with an amino protecting group, preferably a benzoyl group. This compound 9 is then contacted with a palladium catalyst and the desired vinyl e~her. The vinyl ' - ~

.

X 8265A 20 ~:049~

ethers useful in this method include those in which Rc is a Cl-C4 alkyl and Q is hydrogen or an alkyl tin, alkyl or alkoxy boron, zinc halide, or magnesium halide, for example tributyltin. When Q is zinc halide or magnesium halide, it is preferred that Z be a group such as trityl. Ra and Rb can independently be hydrogen, Cl-C6 alkyl, substituted Cl-C6 alkyl, aryl, aryl (Cl-C2) alkyl, substituted aryl, substituted aryl (Cl-C2) alkyl, or C3-C7 cycloalkyl group.
The palladium catalyst used can be palladium powder (black) or Pd(PPh3)4 [where Ph is phenyl]. The Pd(PPh3)4 is commonly used with toluene at reflux. The Pd-black can be used with triphenylphosphine in toluene at reflux or in a mixture of acetonitrile and triethyl amine at about 100C. Similar reactions are reported in ~11. Chem, ~o~. ~n. (1987), Q, 767-768, incorporated herein by reference .

~(~4~
X-826sA 21 Scheme 8 Ra NR1R2 ~ C\ R ~ ORC

Pd - Black/PPh ZN - I or 9 Pd (PPh3) 4 7N

Ra F~a l R C~c~,O RC~c~O

~NR1 R2 HN ~N
:~a In another preparation method depicted in Scheme 9, the 6-iodo derivative ~ can be used to prepare certain 6-acyl compounds directly. This i9 accomplished by contacting the 6-iodo compound with trialkyltin-alkyl complex and car~on monoxide in the presence of a palladium catalyst Pd(PPh3)4 [where Ph is phenyl] as described in the literature for arylhalides.
[A. Schoenberg and R. F. Heck, ~. Orq Ch~m., ~, p.
3327 (1974); and A, Schoenberg, I. Bartoletti, and R.
F. Heck, ~. Or~. Cham., ~, p. 3318 (1974)~. The blockin~ group Z which is preferably benzoyl for this method can ~e removed as described hereinabove to provide cqm~pund I.

J

X-8265A 22 ~9~ 7 ~h~m~
o co~ ~,NRl R2 Z-N R3~nRl Z-N
O ,~/
R7- ~
~ NR1R2 HN
The processes depicted in Schemes l-9 can result in a mixture of products which require purification by standard methods of purfication, for example, crystallization or chromatographic techniques as appropriate.
Scheme lO illustrates a preparation of the s~arting material for reaction Scheme l.

, ~ . . .
., ~ `
, X-826sA 23 Scheme 10 ~ $~f~

~NH2 ~ ~ NHR~ ~N

3,N ~7 R3,N ~ F,3,N lE

~,NH2 ,N

Epoxides of formula ~3 are known in the art or can be prepared from compounds such as ketone 12, which is known to the art, using common rea~ents and techniques. For example, Flaugh, ~ al., ~. Med. Chem~ , ~1, 1746 (1988); Nichols Q~
Org. Prep. a~d ~roG ~ ~ Int., 9, 277 (1977); and Leanna e~ al., T~t. ~ett~, 30, No. 30, 3935 (1989), teach methods of preparation of various embodiments of com-pounds of formula 1~. Those ski1led in the art of organic chemis~ry will recognize tha~ there are four L5 stereoisomers of formula 1~:

x-826sA 24 ~ ~ ~ 9 ~ 7 ~ D ~ ~ O

B lla B L~b B l~c B l~d Formulae L~a and 1~ are herein referred to collectively as the exo-isomers; similarly, formulae 1~ and 13d are the endo-isomers. Leanna ~_al~, ~ara, teach the preparation of epoxides of formula 13 which are substantially exo or substantially endo, as -desired. A preferred starting material is the compound of formula 13 wherein R3 is benzoyl; the most preferred starting material is the mixture of substantially the exo-isomers thereof.
Amino alcohols of formula 1~ are formed by reacting an epoxide of formula 13 with an amine of formula R8~2, where R8 can be hydrogen, a Cl-C4 alkyl, or a Cl-C~ alkyl substituted with one to three groups selected from halogen, nitro or phenyl. Such amines are readily available. Opening of the epoxide ring proceeds substantially regiospecifically with the amino group at the 5-position and the hydroxyl group at the 4-position. The reaction is also stereospecific in the sense that stereoisomers of formulae 14a-d are predictably formed from, re-spectively, stereoisomers of formulae l~a-d.
~HR8 NHR~ NHR8 NHR8 OH $~

B L4a B ~Lb B ~c ~3 ~Ld 25A stereoselective synthesis of the amino alcohol of formula 1~, and hence of all the subsequent 7~j ~-8255A 25 intermediates and products of Scheme 10, can be effected by using a substantially pure enantiomer of an amine of the formula R8NH2, wherein R8 contains at least one chiral center. A particularly preferred amine is (+) or (-) l-phenylethylamine. The diastereomers of the resulting amino alcohol can then be separated by a number of means known in the art, for example by chromatography or crystallization. Suitable solvents for recrystallization include those such as diethyl ether, butanol, and mixtures of hexane and ethyl acetate. An alternative method of achieving a stereospecific synthesis comprises conversion of all the diastereomers of formula 1~ to corresponding diastereomers of formula 1~, followed by the separation of said diastereomers of formula 1~; that alternative method is discussed below. If a stereoselective syn-thesis is not desired, then separation of the stereo-isomers of the amino alcohol of formula 1~ is not required and the amine R8NH2 need not be optically active.
A particularly efficient stereoselective process for a highly preferred compound of formula 14, l-benzoyl-4-hydroxy-5-(1-phenylethyl)amino-1,2,-2a,3,4,5-hexahydrobenz[cd]indole, comprises the reaction of a mixture of substantially the exo-isomers of the corresponding epoxide of formula 1~, or a mixture of substantially the endo-isomers of the corresponding epo~ide of formula 1~, with a substantially pure enantiomer of l-phenethylamine in the solvent butanol and the subseguent selective crystallization of one of the two isomers of the amino alcohol. The temperature of the reaction is preferably from about 50 to about 150C, more preferably in the range of about 80 to about L00C.
After the reaction is complete, as determined for example by thin layer chromatography or liquid . ~

X-8265A 26 ~9~7~

chromatography, the desired amino alcohol is crystallized at about -20 to about ~0C; the preferred temperature for the crystallization is about 0 to about 15C. Therefore this process has the valuable attribute that the reaction and the separation of stereoisomers occur efficiently in a slngle step. By the proper selection of the epoxide isomers, exo or endo, and the enantiomer of l-phenylethylamine, R or S, one can determine which of the stereoisomers of the compound of formula 14 precipitates from the reaction mixture. For example, a preferred stereoisomer of l-benzoyl-4-hydroxy-5-(1-phenylethyl)amino-1,2,2a,3,4,5-hexahydrobenz[cd]indole, the (2a-S,4-R,5-R)-isomer can be selectively prepared by reacting the exo-epoxides with S-l-phenylethylamine.
A number of methods of forming aziridines such as those of formula 1~ from amino alcohols such as those of formula 14 are known to the art. Two examples are the use of diethyl azodicarboxylate and triphenylphosphine (O. Mitsunobu, 9~n~h9EiQ, January, 1981, page 1), and the use of bromine and triphenylphosphine (J. P.
Freemer and P. J. Mondron, a~n¢h~gi~, December, 1974, page 894).
A particularly efficient alternative to the above mathods involving treating a compound of formula 1~ with a tertiary amine in an inert solvent followed by the addition of methanesulfonyl chloride. The stereoisomers l~a-d of the a2iridine 1~ arise respectively from the stereoisomers of formula l~a-d with retention of configuration at any chiral center in the substituents R3 or R8 as well as at position 2a:

X-8265A 27 ~ 76 R8 N,R ,R8 ~N' ~H r ~ H r H
B ~,~a B ~b B ~,~c B L~d Suitable tertiary amines include those of the formula (R9)3N, where the R9 group~ are independently C1-C~
alkyl. Suitable solvents are chlorinaked hydro-carbons such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; aromatic hydrocarbons such as benzene, toluene, and the xylenes;
and ethers such as tetrahydroEuran, diethyl ether, and methyl ~-butyl ether. The reaction can be conducted at a temperature from about -35 to about 45C. In ~he preferred embodiment, the amino alcohol is treated with triethylamine in methylene chloride a~ about -20 to about 0C, then the reaction mixture is warmed to about 15 to about 35C for ~he completion of the reaction.
If desired, tne product, an aziridine of formula 1~, can be crystallized from an appropriate solvent such as acetonitrile or isopropanol after an aqueous workup.
In the event that R8 contains at least one chiral center in substantially a single stereoconfiguration, the individual stereoisomers of the aziridine of formula 1~ can be separated by methods such as chromatograp~y and crystallization, thereby providing a stereospecific synthesis of the aziridine of formula l~
and subsequent products.
The aziridine ring can b~ opened to form an intermediate secondary amine of formNla 16. A number of methods of opening aziridines are commonly known. It is, however, crucial that the method used for opening the aziridine to form a secondary amine of formula 16 be ,. ~ ..

. :

X-8~65~ 28 Z ~

substantially regiospecific, i.e., the aziridine must be opened to form substantially the ~-amino compound rather than the 5-amino compound. One such method is catalytic hydrogenolysis as taught by Y. Sugi and S. Mitsui, Bull. Chem.~oc. Ja~ , pp. 1489-1496 (1970).
Catalysts which are suitable are the usual hydrogenation and hydrogenolysis catalysts, such as the noble metal catalysts; the preferred catalyst is palladium. Suitable solvents include hydrocarbons such as hexanes and heptanes; aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, and t-butylbenzene; alcohols such as methanol, ethanol, and isopropanol; and mi~tures of solvents such as acetic acid mixed with said alcohols. Preferred solvents for preparing the compound of formula 1~, wherein R3 is benzoyl, and R8 is l-phenylethyl, include glacial acetic acid or a mixture of methanol and phosphoric acid~ The source of hydrogen can be an atmosphere of elemental hydrogen supplied at a pressure of about 1 atmosphere or higher, or the source of hydrogen can be compounds which are suitable to serve as hydrogen donors in a catalytic transfer hydrogenolysis reaction, such as formic acid, cyclohexene or hydrazine. The preferred hydrogen source is an atmosphere of hydrogen gas supplied at about 1 to about 10 atmospheres pres-sure. The t~mperature of the reaction may be from about -20 to about 80C; the preferred temperature for the hydrogenolysis of the aziridine wherein R3 is ~enzoyl and R8 is l-phenylethyl is about -20 to about 0C.
The con~ersion of compounds of formula 1~ to compounds of formula 1~ proceeds without disturbing the stereochemical configuration of the chiral centers at the 2a- or 4- positions of the formula 1~ or of the chiral centers that may be present in any of the substituents.

7~i ~-8265A 29 If desired, the compound of formula 16 can be isolated by the usual methods such as crystallization. The secondary amine at position 4 of formula 16 can be converted to a primary amine of formula 17 b~ a number of methods known to the art of organic chemistry, or alternatively the secondary amine itself can be isolated. However, a preferred method is to convert the secondary amine of formula 16 to the primary amine of formula 11 without isolating the secondary amine, but rather by simply continuing without interruption the hydrogenolysis reaction that produced the compound of formula 1~. Therefore, the preferred solvent and catalyst are the same as those for the preparation of the secondary amine of formula 1~. It may be desirable to conduct the hydrogenolysis of the secondary amine of formula 1~ at a different temperature or a different pressure or different temperature and pressure than the hydrogenolysis of the aziridine of formula l.S. For the hydrogenolysis of the preferred compound of formula 1~ wherein R3 is benzoyl and R8 is 1-phenylethyl, the preferred temperature and pressure are about 50~ to about 60C and about 1 to about 20 atmospheres. Under th~se conditions, the hydrogenolysis of compounds of formula 1~ to compounds of formula 17 proceeds without disturbing the stereochemical configuration of the chiral center at the 4-position.
The isolation of the compound of formula 17 can be accomplished by the usual methods such as crystallization.
If desired, the compound of formula 17 can be further purified, for example by recrystallization.
The compound of formula 1~ can be halogenated to provide, for example, the 6-bromo or 6-iodo derivative 1~.
Iodination of compound 17 can be accomplished by using iodine and orthoperiodic acid in the presence of an acid such as sulfuric acid or trifluoroactic acid, in a solvent such as , ~
, 3~
X-~265A 30 acetic acid. Another method of iodination involves the use of N-iodosuccinimide in the presence of trifluoroacetic acid. The 6-bromo derivative can be prepared using bromine in acetic acid or using N-bromosuccinimide.
Of course, as those skilled in the art will reco~nize, variations of any of the Schemes discussed herein may be desirable or necessary for certain em-bodiments of the invention. Such variations are con-templated as within the scope of the present invention.
Compounds of Formula I can be prepared from the appropriate compound of formula 1~, whether it exists as a mixture of stereoisomers or as a substantially pure diastereomer using common reagents and methods well known in the art. A preferred intermediate to the compounds of the instant invention is the 6-bromo-derivative of 1~ although the 6-iodo derivative is preferred if the carbonylation reaction of Scheme 8 is used. PreEerably R~ is an amino-blocking group such as benzoyl. Amino blocking groups can be added, if desired, to the 4-amino substituent using such methods as those disclosed by Gree~e, su~ra, and Barton, su~ra.
Alkyl groups can be added, if desired, to the 4-amino substituent using such common methods as reac~ion of the 4-amine with the appropriate halide as discussed by Morrison and Boyd, Chapter 22, O~aanic Chemistry, Third Edition, Allyn and Bacon, Boston, 1973. If desired, the benzoyl group can be removed from the 1-position using known methods and optionally replaced with other amino-protecting groups. The amino-protecting groups and alkyl groups can be added either before or after the bromination, as desired.
The 4-amino-6-bromohexahydrobenz[cd]indole startin~ materials used to prepare the compo~nds of the invention can be readily prepared by other processes such as disclosed in United States Patent No. 4,576,959 and EPO ~pplication 153083 of Flaugh, each of which is .

: ` :
.

, 7~
X-82~s~ 31 incorporated herein by reference in its entirety.
The following examples further illustrate the preparation of the compounds of this invention. The examples are provided for purposes of illustration only and are not to be construed as limiting the scope of the instant invention in any way.
The terms and abbreviations used in the instant examples have their normal meaning unless otherwise designed, for example, "C" refers to degrees celsius; ~N~ refers to normal or normality; "mmol~
referes to millimole; "g" referes to gram; "ml" means milliliter; "M" refers to molar; "min" refers to minutes; ~hr~ refers to hours; "EtOAc refers to ethyl acetate; "RT" refers to room temperature; "sat'd" means saturated; ""ppt" means precipitate; "Et2O" re~ers to ethyl ether; "THF" refers to tetrahydrofuran; "MsCl" refers to mesyl chloride; "NMR" refers to nuclear magnetic resonance;
"IR~ refers to infrared spectroscopy; "U.V." refers to ultraviolet spectroscopy; and "m.s." refers to mass spectrometry.

Example 1 Preparation of mixture of (2aS,4R)-, (2aR,4S)-l-Ben~oyl-~-cyano-4-(di-n-propylamino)-1,2,2a,3,~,5-hexahydrobenz[cd]indole.
To a solution of dimethyl formamide (lOOmL) containing a mixture of (2aS,4R)- and (2aR,4S)-1-benzoyl-6-bromo-4-(di-n-propyl-amino)hexahydroben2[cd]indole under a N2 atmosphere were added 3.4g (37.5 mmol) of CuCN and 7.lg (37.5 mmol) of CuI. The reaction mixture was then stirred at 140C for 6 hours. The reaction mixture was poured onto ice, diluted with water, CH2C12 was added and the mixture stirred for 30 minutes. The mixture w~s filtered through a diatomaceous earth (tradename "Celite") pad and the filtrate was extracted twice with CH2Cl2. The organic ~olution was dried o~er MgSO4 and .. : ~ . ~
.
!. ~, . ' .

X-8265A 3~ ~33L~7 then evaporated to provide 4g of solid. Chromatography of this crude product over silica gel with 1:19 MeOH/CH2Cl2 as eluent gave 3g (62%) of product.

~Im~
Preparation of mixture oE (2aS,4R)-, (2aR,4S)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.
To a stirred solution of 4.8g (0.0124 mol) of l-benzoyl-6-cyano-~-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole prepared as in Example 1 in 200 mL of ~HF cooled to -78C under N2 atmosphere, was added 16 mL (0.025 mol) of 1.6~ solution of n-butyl-lithium in hexane. The reaction mixture was stirred at -78C for 30 minutes and then allowed to warm to -20C.
To the reaction mixture was added 100mL in 1~ HCl. The mixture was extracted once with ethyl ether. The acidic solution was made alkaline with the addition of cold 5N NaOH. The basic mixture was extracted twice with CH2C12. The coIribined organic solution was washed with saturated aqueous NaCl solution. qhe CH2C12 solution was dried over ~qgS04 and evaporated to give 4g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 3g (85~) of product as an oil, which upon standing solidified.

E~sam~
Preparation of mixture of (2aS,4R)-, (2aR,4S)-6-acetyl-4-(di-n-propylarnino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.
A solution of 0.5g (1.8 ~nol) of 6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,s-hexahydrobenz[cd]indole prepared as in Exam;ple 2 in 75mL of benzene was treated with 5mL of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refl~n~ea for 2 days.
The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of saturated aqueous NH4Cl solution. The benzene layer was separated and washed once with saturated aqueous NaCl solu~ion. m e organic solution was evaporated to an oil. The oil was dissolved in 25mL of 5N HCl and the solution was stirred at room temperature for 30 minutes. The acidic solution was made alkaline with the addition of excess concentrated aq~leous NH40H
solution. The basic mixture was extracted twice with CH2Cl2. The combined organic solution was washed once with saturated aqueous NaCl solution and dried over MgSO4. The CEI2C12 solution was evaporated to yield 0.5g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 0.4g (75%) of product as an oil, which upon standing solidified, m.p.
76-77C.
AnalySiS for (ClgH28N2O) Theory: C, 75.96; H, 9.39; N, 9.32 Found: C, 75.66; H, 9.33; N, 9.38 NMR: (300 M~z, CDC13) d 0.89 (t, 6H, CCH3), 1.46 (mult, 5H, 3a-H & CH2Me), 2.16 (br d, lH, 3~-H), 2.49 (mult, 4H, CH2Et), 2.50 (s, 3H, COCH3), 2.87 (dd, lH, 5a-H), 3.15 (mult, lH, 2~-h), 3.19 (mult, 2H, 2a-H &
2~-H), 3.~2 (dd, lH, 5~-H), 3.73 (mult, lH, 4-H), 4.04 (br s, lH, l-H), 6.43 (d, lH, 8-H), 7.63 (d, lH), 7-H).
M.S.: m/e = 300 (fd).

Exa~
Preparation of (2aR,4R)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole A. A mixturs of l-benzoyl-4,5-(endo)epox~-1,2,2a,3,4,5-hexahydrobenz[cd]-indole (2lg, 0.076mol) and (+)-R-l-phene~h~lamine (18g, 0.15mol) in 400ml of n-butanol was refluxed under N2 for 16h. The reaction was concentrated in , vacuo ~o provide 30g of an oil as an equal mixture of two dias~ereomeric amino alcohols.
The mixture of amino alcohols was dissolved in 300ml of CH2Cl2 and Et3N (30g, 0.225mol) was added at once under N2. The reaction mixture was cooled to -10C then MsCl(12.9g, 0.011) was slowly added dropwise. The rate of addition was such as to maintain a reaction temperature between -10 and 5C. Upon complete addition of MsCl, the reaction mixture was stirred for an additional 30min a~ -5C
and then 30 min at ambient temperature. To the reaction mixture was added 200ml of water and the mixture was stirred.
The CH2Cl2 solution was separated and washed successively sat'd NaHCO3 sol and brine sol. The organic sol was dried (MgSO4) and concentrated to dryness to provide a mixture of two diastereomeric aziridines. The mixture was separated by preparative HPLC (silica gel; hexanes/EtOAc gradient). The first diastereomer of the aziridines to be eluted was designated isomer l; 6.6g, mp 162-163C from i-PrOH. The second diastereomer to be eluted was designated as isomer ~;
7.4g, mp 144-145C from isopropyl alcohol.

B. (2aR,4R)-4-amino-1-benzoyl-1,2,2a,3,4,5-hexahydrobenzl[cd]indole A solution of aziridine isomer 1 (9.4g,0.025mol) in 90ml of glacial acetic acid was hydrogenated at 60psi and at 60C over 5% Pd/C f~r 16h. The reaction mixture was filtered and the filtrate was evaporated to a residual oil. The residue was dissol~red in lN HCI and the acidic mixture was extracted once wi~h EtOAC. The acidic solution was made alkaline with addition of concentrated N~40H. The basic mixture was extracted with CH2C12. The CH2C12 solu~ion was washed with brine solution and dried (MgSO4). The organic solution was evaporated to dryness to provide 2aR,4R-4-amino-1-benzoyl-1,2,2a,3,4,5-hexhydrobenz[cd] indole; 5.2g as an oil.

- X-8265A 35 ~ 7~3 C. (2aR, 4R)-4-amino-1-benzoyl-6-bromo-1,2,2a,3,~,s-hexahydrobenz[cd]indole A solution o~ (2aR, 4R)-4-amino-1-benzoyl-1,2,2a,3,g,5-hexahydro-benz[cd]indole(5.2g,0.019mol) and sodium acetate (6.2g,0.076) in 40mL glacial acetic acid (HOAc) and 10mL of MeOH was cooled to 10C. to the reaction mixture was added dropwise a solution of bromine(3g, 0.019mol) in 10mL oE glacial HOAc. The reaction temperature was maintained at 10C during addition of the bromine. The reaction was then stirred at ambient temperature for lh. The solvents were evaporated and the residue was dissolved in water. The acidic solution was made alkaline with cold 50%
aqueous NaOH. The basic mixture was extracted twice with CH2C12. The organic solution was washed with brine solution, dried (MgSO4) and concentrated in vacuo to provide 6.8g (2aR,4R)-6-bromo compound as an oil.

D. (2aR, 4R)-l-benzoyl-6-bromo-4(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole A reaction mixture of (2aR, 4R)-4-amino-1-benzoyl-6-bromo-1,2,2a,3,4,5-hexahydrobenz[cd]indole(6.8g, 0.019mol), K2CO3(8.2~g, 0.06mol) and n-propyliodide(10.2g, 0.06mol) in 200mL of CH3CN was stirred at reflux temperature ~or 16h.
The reaction mixture was filtered and solvent was evaporatQd.
The residue was dissolved in EtOAc and the solution was extracted with dilute HCl. The acidic solution was made alkaline with concentrated NH40H. Th~ basic mixture was extracted with EtOAc. The organic solution was washed with brlne solution and dried (MgSO4). ~he EtOAc was evaporated to provide a residual oil. Chromatography (silica gel-EtOAc) gave product, 2.4g.

, ~ .

':
.
, : ~

E. (2aR,4R)-l-Benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole To a solution of (2aR,4R)-1-senzoyl-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexa-hydrobenz[cd]indole (2.4g;5mmol) in 100mL of dimethyl formamide (DMF) was added CuCN (1.34g,15mmol) and CuI (2.85g, 15mmol). The reaction mixture was stirred at reflux under a N2 atmosphere for 16hr.
qhe reaction mixture was poured into 500mL of water. The ppt was collected and washed several times with water. The ppt was suspended in dil NH40H and slurried with EtOAc. The whole mixture was filtered thru a celite pad. The EtOAC sol was separated and washed with brine sol. The EtOAc sol was dried(MgSO4) and conc to dryness to provide 1.7g of nitrile as an oil.

F. (2aR,4R)-6-Cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz~cd]indole To a stirred solution of 1.7g (4.4~nol) of (2aR,4R)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[c,d]indole in ~5mL of THF cooled to -78C under a N2 atmosphere was added 5.SmL (8.8~nol) of 1.6M solution of n-BuLi in hexane. The reaction mixture was stirred at -78C
for 30 min. and then allowed to warm to -20C. To the reaction mixture was added 20~L of lN HCl. The mixture was extracted once with Et2O. The acidic solution was made alkaline with the addition of cold 5N NaOH. The baslc mi~ture was extracted twice with CH2C12. The coInbined organic solution was washed with sat'd NaCl solution. The CH2C12 solution was dried over MgSO4 and evaporated to give 1.3g of an oil. Chromatography of this oil over silica gel with EtOAc as eluent gave lg (~096) of product as an oil.

G. (2aR,4R)-1-Trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydro~enz[cd]indole -- X-8265A 37 ~ 7~

To a sol of (2aR,4R~ trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,s-hexahydrobenz[cd~indole (lg, 3.5mmol) and Et3N (354mg, 3.5mmol) in 50mL of methylene chloride was added a sol of triphenylmethyl chloride (trityl chloride)(0.98~,3.5mmol) in 10mL of methylene chloride dropwise at RT. The reaction mixture was stirred for 16hr at RT. The reactlon mixture was extracted with water and cold lN HCl. The organic sol was washed with sat'd NaHCO3 sol and with sat~d brine sol. The organic sol was dried (MgSO4) and conc to dryness in vacuo to give a residue. The residue was slurried with warm hexanes, cooled and filtered to remove insolubles. The filtrate was conc to an oil. The oil was chromatographed (silica gel, 20% EtOAc in hexanes) to provide 1.5g of (2aR,4R)-l-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indole.

H. (2aR,4R)-6-acetyl-4-(di-n-propylamlno)-1,2,2a,3,4,5-hexahydrobenz[c,d]indole A solution of 1.6g(3mmol) (2aR,4R)-l-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz~cd]indole in 100ml of THF was treated with 20mL
of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 16hr. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of sat'd NH4Cl solution. The reaction mixture was extracted with EtOAc. The organic solution was evaporated to an oil. The oil was dissolved in 25mL of 5N HCl and the solution was stirred at room tempera~ure for 30 min. The acidic solution was made al~aline with the addition of excess conc N~40H solution. The basic mixture was extracted twice with EtOAc. The combined organic solution was washed once with satld NaCl solution and dried over MgS04. The EtOAc solution was evapora~ed to yield 0.9g of an oil.
Chromatography of this oil over silica gel with EtOAc as eluent gave 600mg of product. Recryst from hexanes to yield 228mg (-) ketone.
mp 85-~6;[a] D= -4.94(CH30H) Example 5 Preparation of (2aS,~S)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole A. Aziridine isomer ~ from Example 4A (8.5g, 0.022mol) was hydrogenated to provide (2aS,4S)-4-amino-1-benzoyl-1,2,2a,3,4,5-hexahydrobenz~cd]indole(4.5g) as an oil.

B. (2aS,4S)-4-amino-1-benzoyl-6-bromo-1,2,2a,3,4,5-hexahydro~enz[cd]indole Usin~ the procedure of Example 4C, (2aS,~S)-4-amino-1-benzoyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole (4.5g,0.016mol) was halogenated to yield 5.4g (2aS,4S)-6-bromo compound as an oil.
C. (2aS,4S)-1-benzoyl-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole Using the procedure of E~ample 4D, the reaction of (2aS,4S)-4-amino-1-benzoyl-6-bromo-1,2,2a,3,4,5-hexahydrobenz[cd]indole(5.4g, 0.015mol) with n-propyliodide (10.2g, 0.06mol) in the presence of K2CO3(8.28gr 0.06mol) in 200ml of CH3CN gave, after chromatography, 3.lg of product.

D. (2aS,4S)-1-Benzoyl-~-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd~indole Using the procedure of Example 4E, (2aR,4R)-1-benzoyl-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (3.1g, 7~mol) with CuCN (l.g,21mmol) and CuI (4g, 21mmol) in lOOml DMF gave 2.sg of nitrile as an oil.

E. (2aS,~S)-6 Cyano-4-(di-n-propylamino)-1,2,2a,3,4,s-hexahydrobenz~cd]indole The procedure of Example ~F was followed using 2.5g (6.5mmol) of (2aS,4S)-l-benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]-indole and 8.lml (13mmol) n-butyl lithium to provide 1.6g of an oil. Chromatography of the oil over silica gel with EtOAc as eluent gave lg (54%) of product as an oil.
F. (2aS,4S)-l-trityl-6-cyano-4-(di-n-propylamino) -1,2,2a,3,4,5-hexahydrobenz[cd]indole The procedure of Example 4G was followed using the product from Example 4E (lg, 3.5mmol) to provide 1.6g of product.

G. Formation of (2aS,4S)-6-acetyl-4-(di-n-propyl-amino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole The procedure of Example 4X was followed using product from Example 4F (1.6g, 2.9mmol) to provide l.Og of an oil. Chromatography of the oil over silica gel with EtOAc as eluent gave 700mg of product. Recrystallization from hexanes yielded 24Omg of the (~) ketone.
mp 85-86C
[a] D = ~ 5.15(CH30H) ~x~m~Q
Preparation of (+)-(2aS,4R)-6-acetyl-4-(di-n-propylamino) 1,2,2a,3,4,5-hexahydrobenz [cd]indole.
The above described procedure was used to prepare (2aS,4R)-l-benzoyl-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz [cd]indole. The procedures of Example 4 ~ere used to form (+) (2aS,~R)-1-trityl-6-cyano-4-(di-n-propylamine)-1,2,2a,3,4,5-hexah~drob~nz[cd]indole a solution of which (2.4g,4.6mmol) in lOOml of THF was treated with 25m~

X-8265A 40 ~r~

of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 16hr. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of saturated NH4Cl solution. The reaction mixture was extracted with ethyl acetate. The organic solution was evaporated to an oil. The oil was dissolved in 25mL of 5N
HCl and the solution was stirred at room temperature for 30min. The acidlc solution was made alkaline with the addition of excess concentrated NH40H solution. The basic mixture was extracted twice with ethyl acetate. The combined organic solution was washed once with saturated NaCl solution and dried over MgS04. The ethyl acetate solution was evaporated to yield 1.4g of an oil. Chromatography of this oil over silicia gel with ethyl acetate as eluent gave 1.2g (87%) of product. Recrystallization from hexane yielded 840 mg of the product (+)ketone.
mp = 121-122C
[a] D = + 66.60(CH30H) ~am~le 7 Preparation of (-)(2aR,4S)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,s-hexahydroben~[cd]indole The above described procedure was used to prepare (2aR,4S)-l-benzoyl-6-bromo-4-(di-n-propylamino)-1-2,2a,3,4,5-hexahydrobenz[cd]indole. I~te procedures of Example 4 were used to prepare (2aR,4S)-l-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole a solution of which (3.~g,6.smmol) in 100ml of THF was treated with 40mL
of 2.0M methylmagnesium bromide in diethyl ether. ~te reaction mixture was refluxed for 16hr. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of satld NH4Cl solution. The basic mixture was extracted twice with EtOAc. ~he combined organic solution was washed once with sat~d NaCl solution and dried over ~Q~ 7~

Mg~O4. The EtOAc solution was evaporated to yield l.9g of an oil. Chromatography of this oil over silicia gel with EtOAc as eluent gave 1.8g of product which was recrystallized from hexane to yield 1.4g of product.
mp 120-121C
[a]D = -64.48(CH30H) Examwle ~
Preparation of (~)-(2aS,4R)-6-(2-methylpropanoyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (2aS,4~ trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole was prepared as in Example 6. A solution of this hexahydrobenz[cd]indole (9.5g,0.018mol) in 200mL of THF was treated with 30mL of 2.OM
isopropylmagnesium chloride in diethyl ether. The reaction mixture was refluxed for 16hr. The reaction mixture was cooled and decomposed with addition of 50mL of 5N HCl then warmed for 30min on a steam bath. The acidic mixture was extracted twice with EtOAc. The combined organic solution was washed once with sat~d NaCl solution and dried over MgS04. The EtOAC solution was evaporated to yield l.9g of an oil. Chromatography of this oil over silicia gel with ~OAc as eluent gave 0.9g of product. Recrystallization from hexanes to yield 360mg of product.
mp 87-89C
[a]D = ~52.72(CH30H) ~lm~he ~

Preparation of (-)-6-(2-methylpropanoyl)-~-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole X-826~A 42 The procedure of Example 8 was followed with (-)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (7g,13mmol), isopropylmagnesium chloride (50 mL, 2 molar in ethyl ether), THF (150mL) to give 3.8 g of crude product. Chromatography with silica gel using EtOAc as eluent gave 0.8 g of material whch was recrystallized from hexanes to give 400 mg of product.
mp = 8~-89C
[~]D - -51.0 (CH3OH) Exam~le 1~
Preparation of (-)-(2aR,4S)-6-(propanoyl)-4-(di-n-propylamino)-1,2,2a,3,~,5-hexahydrobenz[cd]indole A solution of (-)-(2aR, 4S)-l-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (1.5g, 2.7mmol) in 200ml of THF was treated with 25 mL of 2.OM
ethylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 16 hr. The reaction mixture was cooled and decomposed with addition of 50mL of 5N HCl then warmed for 30 min on a steam bath. The acidic mixture was extracted with EtOAc. The acidic solution was made alkaline with the addition of excess conc NH40H solution. The basic mixture was extracted ~wice with EtOAc. The combined organic solution was washed once with satld NaCl solution and dried over MgS04. The EtOAc solution was evaporated to yield 0.6g of an oil. Chromatography of this oil over silica gel with EtOAc as eluent gave 0.4g of product. Recrystallization from hexanes gave 300mg (-) ketone.
mp 90-91C
[~]D = -63.68(CH30E) Exam};)1 e l L
Preparation of (+)-(~aS,4R)-6-(pentanoyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole X-8265A 43 ~ ~ 4 ~ ~ 7 A solution of (+)-(2aS,4R)-l-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1.0g, 2mmol) in 4Oml of THF was added dropwise to a solu~ion of n-butylmagnesium iodide (25mmol) in 25mL diethyl ether. Thereaction mixture was refluxed for 16hr. The reaction mixture was cooled and decomposed with addition of 50mL of SN HCl then warmed for 30min on a steam bath. The acidic mixture was extracted with EtOAc. The acidic solution was made alkaline with the addition of excess conc NH40H solution.
The basic mixture was extracted twice with EtOAc. The combined organic solution was washed once with sat'd NaCl solution and dried over MgS04. The EtOAc solution was evaporated to yield 0.4g of an oil. Chromatography of this oil over silica gel with EtOAc as eluen~ gave 70mg of product. Recrystallization from hexane gave 25mg ketone.
mp 104-105C
[a] D = + 35.7(CH30H) Exam~le 12 Preparation of (~)-(2aS,4R)-6-(benzoyl)-4-(di-n-propylamine)-1,2,2a,3,4,5-hexahydrobenz[cd]indole A solution of (+)-(2aS,4R)-l~trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1.5g, 2.7mmol) in 30m~ of THF was treated with 10 mL of 3.0M
phenylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 16hr. The reaction mixture was cooled and decol~posed with addition of 50mL of 5N HCl then warmed for 30min on a steam bath. The acidic mixture was extracted with EtOAc. The acidic solution was made alkaline with the addition of excess conc NH40~ solution. The basic mixture was extracted twice with ~tOAc. The comhined organic solution was washed once with sat'd NaCl solutlon and dried over MgSO4. The EtOAc solution was evaporated to yield 0.6g of an oil. Chromatography of this oil over silica gel with . . , . ~ ~ .
.. , ': ' '- ' ~ :

X-8265~ 44 EtOAc as eluent gave 0.3g of product. Recrystallization from h0xanes gave 360mg (+) ketone.
mp 161-162C
[a]D = + 93.66(CH30H) Exam~le 13 Preparation of (+)-(2aS,4R)-6-(2-phenyle~hanoyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole A solution of (~)-(2aS, 4R)-l-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-he~ahydrobenz[c,d]indole (1.0g,2mmol) in 40mL of THF was added dropwise to a solution of benzylmagnesium chloride (25mmol) in 25mL diethyl ether.
The reaction mixture was refluxed for 16hr. The reaction mixture was cooled and decomposed with addition of 50mL of 5N
HCl then warmed for 30min on a steam bath. The acidic mixture was extracted with EtOAc. The acidic solution was made alkaline with the addition of excess conc NH40H
solution. The basic mixture was extracted twice with EtOAc.
The combined organic solution was washed once with sat~d NaCl solution and dried over MgSO~. The EtOAc solution was evaporated to yield 0.6g of an oil. Chromatography o~ this oil over silica gel with EtOAc as eluent gave 0.4g of product. Recrystallization ~rom hexanes gave 225mg (+) ketone.
mp 104-105C
[~] D = ~ 47.62(CH30H) Preparation of (2aS,4R)-6-ethynyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole l-benzoyl-(2aS,4R)-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (100 mg, 0.205mmol) and trimethyltin acetylene trimethylsilane (272 mg, 1.0 m~ol, 3 eq) was disso]ved in anhydrous toluene (5 mL), to which was then added tetrakis-triphenylphosphine palladium (20 mg, 0.017 mmol, 0.05 eq). The resulting light yellow solution was brought to raflux under N2 atmosphere. Af~er 4 hr, the reaction mixture was cooled to room temperature, filtered and concentrated to dryness. The residue was chromatographed over silica gel with hexanes:ethyl acetate (1:1) to afford the desired product (79mg,84%). This material was dissolved in a 1~ solution (5mL) of tetrabutylammonium fluoride in THF, and stirred at room temperature overnight (12 h). The solution was diluted with EtOAc (10 mL) and rinsed successively with H20 (3xlOmL), brine (10 mL) and dried over Na2SO4. The residue was chromatographed over silica gel with hexanes:ethyl acetate (1:1) to afford a mixture of the 1-benzoyl (61%) and the N-deprotected indoline (33%).
The present compounds of Formula I have been found to have selective affinity for the 5HT receptors in the brain with much less affinity for other receptors. Because of their ability to selectively bind to 5~T receptors, the compounds of Formula I are useful in treating disease states which require alteration of 5-HT1A receptor function but without the side effects which may be associated with less selective compounds. It has been further found that certain of the instant compounds have su~stantial affinity for both the 5-HT1A and 5-HT1D receptors and are useful in treating disease states which can benefit from an alteration of the receptors. The alteration of the 5~T1A and 5HTlD receptors may involve mimicking (an agonist) or inhibiting (an antagonist) the function of serotonin. The disease states include anxiety, d~pression, excess gastric acid secretion, hyper~ension, nausea, sexual dysfunction, cognition, senile dementia, consumptive disorders such as appetite disorders, alcoholism and smoking. The foregoing conditions are treated with a pharmaceutically effective amount of a compound of Formula I.
The term ~'pharmaceutically effective amount", ' ~ ` ~

.

X-8265A 46 ~ ~ ~ 9 7 as used herein, represents an amount of a compound of the invention which is capable of diminishing the adverse symptoms of the particular disease. The par-ticular dose of compound administered according to this invention of course be determined by the particular circumstances surrounding the case, including the compo~md administered, the route oE administration, the particular condition being treated, and similar con-siderations. The compounds can be administered by a variety of routes including the oral, rectal, trans-dermal, subcutaneous, intravenous, intramuscular or intranasal routes. A typical single dose for prophylactic treatment, however, will contain from about 0.01 mg/kg to about 50 mg/kg of the active compound of this invention when administered orally.
Preferred oral doses will be about 0.01 to about 3.0 mg/kg, ideally about 0.01 to about 0.1 mg/kg. When a present compound is given orally it may be necessary to administer the compound more than once each day, for example about every eight hours. For IV administration by bolus, the dose will be from about 10 ~g/kg to about 300 ~g/kg, preferably about 20 ~g/kg to about 50 ~g/kg.
The following experiments were conducted to demonstrate the ability of the compounds of the present invention to interact with the serotonin lA and/or lD
receptors. The affinities of the compounds at the cen~ral 5-HT1A receptors were determined using a modification of the binding assay described by Taylor, ~ . Pharma5s1 EXD. The~. 236:118-125, 1986). Membranes for the binding assay were prepared from male Sprague-Dawley rats (150-250 g). The animals were killed by decapitation, and the brains were rapidly chilled and dissected to obtain the hippocampi.
The hippocampi were either prepared that day or stored frozen (-70C) until the day of prepara~ion. Membranes were prepared by homogenizing the tissue in 40 volumes of ice-cold Tris-HCl buffer (50 mM, pH 7.4 at 22C) using a Techmar , ~ . . ~ . .

X-8265A 47 ~ 7~i Tissumizer (setting 65 for 15 sec), and the homogenate was centrifuged at 39800xg for 10 min. The resulting pellet was then resuspended in the same buffer, and the centrifugation and resuspension process was repeated three additional times to wash the membranes. Between the second and third washes the resuspended membranes were incubated for 10 min at 37C
to facilitate the removal of endogenous ligands. The final pellet was resuspended in 6'7mM I'ris-HCl, pH 7.4, to a concentration of ~ mg of tissue original wet weight/200 ~l.
This homogenate was stored frozen (-70C) until the day of the binding assay. Each tube for the binding assay had a final volume of 800 ~l and contained the following: Tris-HCl (50 mM), pargyline (10 ~M), CaCl2(3 m~), [3H]8-o~-DPAT (1.0 nM), appropriate dilutions of the compound being evaluated, and membrane resuspension eguivalent to 2 mg of original tissue wet weight, for a final pH of 7.4. The assay tubes were incubated for 10 min at 37C, and the contents were then rapidly filtered through GF/s filters (pretreated with 0.5%
polyethylenimine), followed by four one-mL washes with ice cold buffer. The radioactivity trap~ad by the filters was quantitated by liquid scintillation spectromet~y, and specific [3H]8-OH-DPAT binding to the 5-HT1A sites was defined as the difference between [3H]~-oH-DPAT bound in the presence and absence of 10 ~M 5-HT.
The affinity of the particular compound at the 5-HTlA
receptor is expressed as IC50 value, i.e., the concentration required to inhibit 50% of the binding. The IC50 values were determined from 12-point competition curves using nonlinear regression (SYSTAT, SYST~T, INC., Evanston, IL). The results from this determination are provided in Table I.
The affinities of the compounds at the central 5-~T1D
binding sites were determined using a modification of the binding assay described b~ ~euring and Peroutka (~L ~xQSCi.
7:894-903, 1987). Bovine brains were obtained from Pel-Freeze Biologicals, and ~he caudate nuclei were dissected out and frozen at -70C until the time that the membranes were .
.

prepared for the binding assays. At that time the tissues were homogenized in ~0 volumes of ice-cold Tris-HCl buffer (50mM, pH 7.4 at 22C) with a Techmar Tissumizer (setting 65 for 15 sec), and the homogenate was centrifuged at 39,800g for 10 min. The resulting pellet was then resuspended in the same buffer, and the centrifugation and resuspension process was repeated three additional times to wash the membranes.
Between the second and third washes the resuspended membranes were incubated for 10 min at 37C to facilitate the removal of endogenous 5-HT. The final pellet was resuspended in Tris buffer to a concentration of 25 mg of original tissue wet weight/ml for use in the binding assay. Each tube ~or the binding assay had a final volume of 800 ~l and contained the following: Tris-HCl (50mM), pargyline (10 ~M), ascorbate (5.7 mM), CaCl2 (3 mM), 8-OH-DPTA (100 nM to mask 5-HTlA
receptors), mesulergine (100 nM to mask 5-HT1C receptors), [3E~] 5-HT (1.7-1.9 nM), appropriate dilutions of the drugs of interest, and membrane suspension equivalent to 5 mg of original tissue wet weight, for a final pH of 7.4. The assay 20 tubes were incubated for 10 min at 37C, and the contents were then rapidly filtered through GF/B filters (pretreated with 0.5% pulyethylenlmine), followed by four one-mL washes with ice-cold buffer. The radioactivity trapped by the filters was quantitated by liquid scintillation spectrometry, 25 and specific [3H] 5 -HT binding to the 5-HT1D sites was defined as the difference between [3H]5-HT bound in the presence and absence of 10 ~M 5-HT.
The affinities of compounds at the 5 -HTlD receptor are expressed as IC50 values, i.e., the concentration required to inhibit 50% of the 'oinding. These values were determined from 12-point competition curves using nonlinear regression (SYSTAT, SYSTAT, Inc., Evanston, IL)~ The results from this determi.nation are provided in Table I.

TABLE I

Exam~le NQ. ~ A(1) 3 0.63 7.47 4 0.80 236.38 0.31 129.24 6 0.3 6.25 7 6.61 8500.0 8 0.25 1.24 9 54.88 3125.00 9.47 9000-00 12 0.34 1.78 13 0.98 2.7 (1) IC50 in nanomoles per liter The compound of Example 1~ was evaluated for its ability to interact with serotonin lA receptor using the following procedure which is generally set forth in Wong 8 ~1~, J. Neural ~r~nsm., I1, 207-218 (1988). Male Sprague-Dawley rats (110-150 g) from Harlan Industries (Cumberland, IN) were fed a Purina Chow ad libitum for at least 3 days before being used in the studies. Rats were killed by decapitation. The brains were rapidly removed, and the cerebral cortices were dissected out at 4C.
Brain ~issues were homogenized in 0.32M sucrose.
After centrifugation a~ 1000 x g for 10 min and then at 17000 x g for 20 min, a crude synaptosomal fraction was sedimented.
The pellet was suspended in 100 vol of 50 mM Tris-HCl, pH
7.4, incubated at 37C for 10 min, and centrifuged at 50000 x g for 10 min. The process was repeated and ~he final pellet was suspended in ice-chilled 50 mM Tris-HCl, pH 7.4. By the radioligand binding method, sites specifically labeled by tritiated 8-hydroxy-2-dipropylamino-1,~,3,4-X-8265A 50 ~ O ~ 9 ~ 7 ~

tetrahydronaphthalene (3H-8-OH-DPAT) have been identified as 5-HT1A receptors.
Binding of (3H-8-OH-DPAT) was performed according to the previously described method [Wong et al., J. ~eural TLans{n. ~:251-269 (1~85)1. Briefly, synaptosomal membranes isolated from cerebral cortex were incubated at 37C for 10 min. in 2 mL of 50 mM Tris-HCl, pH 7.4; 10 ~M pargyline; 0.6 ~M ascorbic acid; 0.4 nM 3H-8-oH-DPAT; and from 1 to 1000 mM
of test compound. Binding was terminated by filtering samples under reduced pressure through glass fiber (GFB) filters. The filters were washed twice wi~h 5 mL of ice cold buffer and placed in scintillation vials with 10 mL of PCS
(Amersham/Searle) scintillation fluid. Radioactivity was measured with a liquid scintillation spectrometer. Unlabeled 8-OH-DPAT at 10 ~ was also included in separate samples to establish non-specific binding. Specific binding of 3H-8-oH-DPAT iS defined as the difference of radioactivity bound in the absence and in the presence of 10 ~M unlabeled 8-OH-DPAT.
The result is provided in Table II. The value is the IC50, i.e. the concentration in nanomoles of the compound necessary to inhibit the binding of 3H-8-oH-DPAT by 50~.

Table II

E~am~le IC~Q
14 0.5 Experiments were conducted to demonstrate the serotonin against properties of ~he instant compounds.
Certain compounds were evaluated to determine their ability to affect the 5-hydroxyindoles serotonin, 5-hydroxyindole acetic acid (5HIAA) and serum corticosterone, in vivo, using the following procedures.
Compounds in aqueous solution were injected subcutaneously into male albino rats. Rats were decapitated one hour later. Trunk blood was collected and allowed to .~ .
- ~

X-8265A 51 ~ 7~, clot; after centrifugation, serum was stored frozen prior to analysis. Whole brain was removed and frozen on dry ice, then stored frozen prior to analysis. Serum corticosterone concentration was measured spectrofluorometrically (J.H.
Solem and T. Brinch-Johnsen, ~An evaluation of a method for determination of free corticosteroids in minute quantities of mouse plasma," ~ d. J. ~lin~_La~. Invest. (Suppl. 80), 1.14 (1965).) 5-Hydroxyindoleacetic acid (5HIAA) concentration in whole brain was measured by liquid chromatography with electrochemical detection. (Ray W.
Fuller and Kenneth W. Perry, ~Effects of buspirone and its metabolite, ~-(2-pyrimidinyl)piperazine, on brain monoamines and their metabolites in rats", ~ Pharmacol. Exp. Thex.
248, 50-56 (1989).) The results are provided in Table III.
Table III
Brain 5-hydroxyindoles (n moles/g) Serium F~m~le No. Corti~ost2rone (dose m~/R~] erotonin 5~Laa (~g/lnnml) Control 2076 iO.122.13 + 0.10 3.8 + 0.2 Example 6 (0.003) 2.46 ~ 0.141.81 ~ 0.145.8 ~ 1.0 (0.03) 2.99 ~ 0.061.58 i 0.08*10.6 i 2.0*
(0.3) 3.08 i 0.04*1041 i 0.03*42.2 i 1.1*
Example 7 (0.003) 2.75 ~ 0.052.~6 ~ 0.133.8 i 0.5 (0.03) 2.57 ~ 0.101.87 ~ 0.076.5 ~ 2.6 (0.3~ 2.85 ~ 0.081.77 + 0.178.4 i 4.0 Control 1.66 * 0.04L.68 ~ 0.123.4 i 0.2 Example 8 (0.003) 1.88 + 0.05*1.56 ~ 0.103.6 ~ 0.7 (0.03) 2.26 ~ 0.06~1.34 ~ 0.06*27.1 i 6.4*

X-8265A 52 ~49~

(0.3) 2.26 ~ 0.16* L.30 ~ 0~07* 42.0 i 0.4*
Example 9 (0.003) 1.83 ~ 0.08 1.68 + 0.10 4.1 ~ 0.5 (0.03) 1.90 ~ 0.10 1.91 i 0.06 6.0 -~ 1.6 (0.3) 1.69 + 0.06 1.74 ~ 0.04 6.7 ~ 2.0 *Significant difference from control group (P<0.05) The compounds of the present invention are preferably formulated prior to administration. There-fore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable excipient therefor.
The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In making the composi-tions of the present invention, the active ingredient will usually be mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or li~uid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the ~orm of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline .

, ~ :.,' , '' ':

X-8265A 53 ~L~ 7 cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as ~ethyl- and propylhydroxybenzoates, sweetening agents or flavoring agents. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.5 to about 50 mg, more usually about 1 to about 10 mg, of the active ingredient. The term "unit dosage formll refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
The following formulation examples are illus-trative only and are not intended to limit the scope of the invention in any way.
For~ul~ion 1 Hard gelatin capsules are prepared using the following ingredients:
Q~ y (mg/ca~ule) 6-acetyl-4-(di-~-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indole 25 Starch, dried 42 Magnesium stearate _1~
Total 460 ~g The above ingredients are mixed and filled X-8265A 54 ~9~7~

into hard gelatin capsules in 460 mg quanti~ies.

Formulation 2 A tablet formula is prepared using the in-gredients below:
Ouantitv (mq/ta~let) 4-(di-n-propylamino)-6-(2,2-dimethylpropanoyl)-1,2,2a,3,4,5-hexahydrobenz[cd]indole 25 Cellulose, microcrystalline 625 Colloidal Silicon Dioxide10 Stearic acid 5 m e components are blended and compressed to form tab]ets each weighing 665 mg.

Formulatio~_~
A dry powder inhaler formulation is prepared containing the following components:
Weight 4-(diethylamino)-6-propanoyl-1,2,2a,3,4,5-hexahydrobenz[cd]-indole 5 Lactose 95 The active compound is mixed with the lactose and the mixture added to a dry powder inhaling ap-plicance.

Formul~ion 4 Tablets each containing 60 mg of active ingredien~
are made up as follows:

4-(n-propylamino)-6-~2-methyl-propanoyl)-l,2,2a,3,4,5-hQxahydro-benz[cd]indole tartrate salt 60 mg Starch 45 ~g Microcrys~alline cellulose35 mg : . ~ .

X-8265A 55 ~.9~7~

Polyvinylpyrrolidone (as 10~
solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mq Total 150 mg The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylp~rrolidone is mixed with the resultant powders which are then passed through a No. 4 mesh U.S. sieve. The granules so produced are dried at 50-60C and passed through a No.
16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Formulation ~
Capsules each con~aining 20 mg of medicament are made as follows:
(2aS,4R)-4-~di-n-propylamino)-6-(2,2-dimethylpropanoyl)-1,2,2a,3,4,5-hexahydrobenz-~cd)indole 20 mg Starch 163 mg Magnesium stearate Total 190 mg The active ingredient, cellulose, starch and magnesium ste~rate are blended, passed through a No.
20 mesh U.S. sieve, and filled into h~rd gelatin capsules in 190 mg quantities.

' :~ ~ ' -~ X-8265A 56 ~049~7&i Fonmulation_6 Suppositories each containing 225 mg of active ingredient are made as follows:
54-(di-n-propylamino)-6-benzoyl-1,2,2a,3,4,S-hexahydrobenz[cd]-indole 225mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No.
60 mesh U.S. sieva and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nomi.nal 2 g capacity and allowed to cool.

Formula~ion 7 Suspensions each containing 50 mg of medicament per 5 mL dose are made as follows:
1-methyl-4-(n-propylamino)-6-(3-methylbutanoyl)-1,2,2a,3,4,5-hexahydrobenz~cd]indole 50 mg Xanthan Gum 4 mg Sodium carboxymethyl cellulose (11%) Microcrystalline Cellulose (89%) 50 mg Sucrose 1.75 g Sodium Benzoate 10 mg Flavor q.v.
Color q.v~
Purified water to 5 mL
The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solu~ion of the microcrystalline cellulose and sodium carboxymethyl-cellulose in water. The sodium benzoate, flavor andcolor are diluted with some of the water and added with :

X-8265A 57 ~49~7~

stirring. Sufficient water is then added ~o produce the required volume.

Formula~ion 8 Capsules each containing 150 mg of medicament are made as follows:
4-(di-n-propylamino)-6-acetyl-1,2,2a,3,4,5-hexahydrobenz[cd]-indole50 mg lo Starch507 mg Magnesium stearate 3 mq Total 560 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quant~ties.

: : .

Claims (20)

1. A compound of the Formula wherein:
R1 is hydrogen, C1-C4 alkyl, C3-C4 alkenyl, cyclopropylmethyl, phenyl-substituted (C1-C4 alkyl), -C(O)R4, -(CH2)nS(C1-C4 alkyl), or -(CH2)nC(O)NR5R6;
R2 is hydrogen, C1-C4 alkyl, C3-C4 alkenyl, or cyclopropylmethyl;
R3 is hydrogen, C1-C4 alkyl or an amino-blocking group;
n is 1-4;
R4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1 - C4 alkoxy or phenyl, R5 and R6 are independently hydrogen, a C1-C4 alkyl, or a C5 - C8 cycloalkyl;
A is C=O, CHOH or C?C;
R7 is C1-C8 alkyl, substituted (C1-C8 alkyl), aryl, substituted aryl, aryl (C1-C4 alkyl), substituted aryl (C1-C4 alkyl), C3-C7 cycloalkyl-substituted methyl, or C3 - C7 cycloalkyl, with the proviso that when A is C?C then R7 is C1-C7 alkyl, substituted (C1-C7 alkyl), aryl, aryl (C1-C3 alkyl), substituted aryl, substituted aryl (C1-C3 alkyl), or C3-C7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1 wherein A is C=O;

X-8265A- (EPO) -59-R1 and R2 are independently hydrogen, C1-C4 alkyl, C3-C4 alkenyl, -(CH2)nS(C1-C4 alkyl) or cyclopropylmethyl;
R3 is hydrogen or C1-C3 alkyl; n is 2-4; or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 2 wherein:
R7 is C1-C4 alkyl, C1-C4 alkoxy-substituted (C1-C4 alkyl), phenyl, phenyl (C1-C4 alkyl), halo-substituted phenyl (C1-C4 alkyl) or C3-C7 cycloalkyl or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 1 wherein A is C=O; R1 and R2 are independently C2-C3 alkyl; R3 is hydrogen, R7 is C1-C3 alkyl; and pharmaceutically acceptable salts thereof.

5. The compound of Claim 4 wherein R1 and R2 are each n-propyl; R7 is methyl or ethyl; and pharmaceutically acceptable salts thereof.

6. A compound of Claim 1 selected from the group consisting of 4-(di-n-propylamino)-6-acetyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 4-(di-n-propylamino)-6-(2,2-dimethylpropanoyl)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 4-(diethylamino)-6-propanoyl-1,2,2a,3,4, 5 -hexahydrobenz [cd]indole; 4-(di-n-propylamino)-6-benzoyl-1,2,2a,3, 4,5-hexahydrobenz [cd]indole; 4-(n-propylamino)-6-(2-methylpropanoyl)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 4-(n-propylamino)-6-(3-methylbutanoyl)-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 4-(di-n-propylamino)-6-benzoyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole; 4-(N-n-propyl-N-cyclopropylmethyl)amino-6-propanoyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole; and phanmaceutically acceptable salts thereof.

7. A substantially pure stereoisomer of the compound of Claims 1 to 6 or a pharmaceutically acceptable salt thereof.

X-8265A-(EPO) -60-

8. The stereoisomer of Claim 7 wherein the configuration at position 2a is S and at position 4 is S or position 2a is R and position 4 is R.

9. The compound of Claim 7 which is (2aS,4S)-4-(di-n-propylamino)-6-acetyl-1,2,2a,3,4,5-hexahydro-benz[cd]indole.

10. The compound of Claim 7 which is (2aR,4R)-4-(di-n-propylamino)-6-acdetyl-1,2,2a,3,4,5-hexahydro-benz[cd]indole.

11. The compound of Claim 7 which is (2aS,4S)-4-(di-n-propylamino)-6-(2-methylpropanoyl)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.

12. The compound of Claim 7 which is (2aR,4R)-4-(di-n-propylamino)-6-(2-methylpropanoyl)-1,2-2a,3,4,5-hexahydrobenz[cd]indole.

13. A compound of Claim 1 wherein: A is C?C;
R1 and R2 are independently hydrogen, C1-C4 alkyl, C3-C4 alkenyl, or cyclopropylmethyl;
R3 is hydrogen, C1-C4 alkyl or an amino-blocking group;
R7 is C1-C7 alkyl, substituted (C1-C7 alkyl), aryl, aryl (C1-C3 alkyl), substituted aryl, substituted aryl (C1-C3 alkyl) or C3-C7 cycloalkyl; or a pharmaceu-tically acceptable salt thereof.

14. A compound of Claim 13 wherein:
R1 and R2 are independently C1-C3 alkyl;
R3 is hydrogen; and R7 is C1-C7 alkyl, alkoxy-substituted (C1-C7 alkyl), phenyl, phenyl (C1-C3 alkyl), halo-substituted phenyl (C1-C3 alkyl) or C3-C7 cycloalkyl.

15. A substantially pure stereoisomer of the compound of Claim 13 wherein the configuration at X-8265A-(EPO) -61-position 2a is S and at position 4 is S or at position 2a is R and position 4 is R.

16. A compound of Claim 1 wherein: A is CHOH;
R1 and R2 are independently hydrogen, C1-C4 alkyl, C3-C4 alkenyl, or cyclopropylmethyl;
R3 is hydrogen, C1-C4 alkyl, or an amino-blocking group;
R7 is C1-C8 alkyl, substituted (C1-C8 alkyl), aryl, substituted aryl, aryl (C1-C4 alkyl), substituted aryl (C1-C4 alkyl), or C3-C7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

17. A compound of Claim 16 wherein:
R1 and R2 are independently C1-C4 alkyl;
R3 is hydrogen or an amino-blocking group selected from the group consisting of benzoyl, benzyl and triisopropylsilyl.

18. A pharmaceutical formulation comprising as an active ingredient a compound as claimed in any one of Claims 1 to 17, associated with one or more pharmaceutically acceptable excipients therefor.

19. A compound as claimed in any one of Claims 1 to 17 for use as a pharmaceutical.

20. A process for preparing a compound as claimed in any one of Claims 1 to 17 wherein R3 is hydrogen, which process comprises hydrolyzing or hydrogenating the compound when R3 is an amino blocking group.